Catalytic asymmetric isomerization/hydroboration of silyl enol ethers

Abstract

Asymmetric remote hydroboration of olefins has emerged as an efficient strategy for the construction of chiral boronic esters. Conventional asymmetric alkene isomerizations rely on directing groups (OH, NR₂, carbonyl) for thermodynamic control via (hyper)conjugation, but their use restricts substrate scope and risks β-heteroatom elimination with transition-metal catalysts. We here reported a catalytic asymmetric isomerization/hydroboration of silyl enol ethers under mild conditions, enabling the efficient synthesis of enantioenriched boryl ethers. The chiral borylether products enable efficient access to valuable 1,n-diols and 1,n-amino alcohols, prevalent in bioactive molecules, and facilitate late-stage functionalization of complex architectures. Preliminary mechanistic studies reveal that this reaction involves a nondissociative chain-walking process and that the β-H elimination may contribute to the rate-limiting step.

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Introduction

Enantioselective transformation of alkenes plays an important role in asymmetric synthesis due to their ready availability, natural abundance, and frequent use as prochiral precursors.^1a To date, transition-metal-catalyzed enantioselective functionalization of alkenes primarily occurs at the native positions of C=C bonds through migratory insertion, nucleophilic or electrophilic addition, encompassing well-established methods such as asymmetric hydrogenation,¹ hydrofunctionalization,² and difunctionalization³ (Fig. 1a, mode I). The organometallic intermediates I generated in the transition-metal-catalyzed functionalization of olefins may alternatively go through β-hydride elimination and reinsertion, resulting in positional olefin isomerization and the formation of a chiral center at the native C=C bond position, namely asymmetric functionalization-isomerization shown in Fig. 1b (Fig. 1b, mode II). However, this mode usually requires functional groups such as OH, NR₂, Ar, or carbonyl groups to provide thermodynamic driving force through the formation of (hyper)conjugated isomers.⁴ For instance, catalytic enantioselective isomerization of alkenes (Fig. 1b, R = H) is mainly limited to allylic amines, alcohols (or ethers), and homoallylic alcohols, as demonstrated by Noyori,⁵ Fu,⁶ Wendlandt,⁷ Zhao,⁸ and others.⁹ Similarly, the enantioselective functionalization-isomerization (Fig. 1b, R ≠ H) is primarily restricted to alkenyl alcohols to provide carbonyl compounds with a remote newly formed stereocenter, as shown in the work of the Sigman group.¹⁰ However, catalytic asymmetric isomerization functionalization of heteroatom substituted-alkenes is much less developed because the heteroatoms might go through β-heteroatom elimination rather than β-hydride elimination,¹¹ limiting their applications in organic synthesis. Therefore, the development of new strategies for enantioselective isomerization-functionalization of heteroatom-substituted alkenes is highly desirable.

Fig. 1 (a) Enantioselective native functionalization of alkenes. (b) Enantioselective functionalization-isomerization of alkenes. (c) Enantioselective isomerization-functionalization of alkenes. (d) This work.

The catalytic asymmetric isomerization of alkenes often necessitates a functional group as the driving force (Fig. 1b, mode II). However, endergonic isomerizations can also^4,12 be facilitated by an irreversible terminal-selective functionalization,¹³ enabling remote C(sp³)−H bond functionalization¹⁴ (Fig. 1c). This isomerization-remote functionalization process has shown significant progress in recent years as it offers rapid access to value-added functional molecules from readily available feedstocks.^4,15 Nonetheless, the enantioselective isomerization-remote functionalization of alkenes remains relatively underexplored and poses challenges in stereoselectivity and regioselectivity control, particularly for heteroatom-substituted alkenes¹⁶ (Fig. 1c, mode III). Building on our previous work in organoboron chemistry,¹⁷ including enantioselective native hydroboration¹⁸ and remote C(sp³)−H borylation^14e of silyl enol ethers, we report a catalytic and enantioselective remote borylation of silyl enol ethers derived from ketones. This strategy addresses thermodynamic challenges, β-oxygen elimination, and regio- and enantioselectivity control to yield enantioenriched borylethers with synthetic utility (Fig. 1d).

Results and discussion

We initiated our investigation using silyl enol ether (Z)-1a′ as the model substrate, [Rh(cod)Cl]₂ as the catalyst, LiOAc as the base, and HBpin as the hydroboration reagent. Initially, a variety of chiral ligands were examined. As shown in Fig. 2, entries 1–6, although no reaction was observed with ligands (R,R)-Sadphos (L1) and (R)-BINAP (L2), the desired product was obtained in 55% yield albeit with 55 : 45 er in the presence of (R,R)-BenzP* (L3). Based on these results, various sterically bulky and electron-rich chiral bidentate phosphine ligands, including (R,R)-QuinoxP* (L4), (R,R)-Ph-BPE (L5), and (R,R,R,R)-OMe-BIBOP (L6) were screened. The enantiomeric ratio was improved to 65 : 35 with (R,R)-QuinoxP*, while (R,R)-Ph-BPE (L5) gave the racemic product. Pleasingly, both the yield (90%) and the enantioselectivity (70 : 30 er) increased when (R,R,R,R)-OMe-BIBOP (L6) was employed. Encouraged by this delightful result, the analogue of BIBOP was studied.¹⁹ As depicted, the substituents on the BIBOP have a great effect on the yields but only a subtle influence on enantioselectivity (L7–L15). Specifically, alkoxy groups on the BIBOP ligands are crucial for the reactivity of the Rh catalyst, as no product was obtained when R = H (L7). However, the enantiomeric ratio fluctuated around 65 : 35 regardless of the alkoxy substituents (L8–L13). Aromatic substituents were also used (L14, L15), but no improvement in results was achieved (see more details in the SI). We then turned our attention to investigating the reaction temperature (Fig. 2, entry 7). As expected, enantioselectivity increased as the reaction temperature decreased. Next, various silyl groups were also optimized. As shown, the er improved with increasing steric hindrance of the silyl group (Fig. 2, entries 7–11), and the super silyl (SiTMS₃) gave the highest er (88 : 12, Fig. 2, entry 11). The solvent effect was also surveyed. The use of DME and dioxane as solvents led to diminished yields, although no erosion in enantiopurity was observed (Fig. 2, entries 12–15). To our delight, a mixture solvent of THF/DCE (Fig. 2, entry 14) provided significantly better results both in yield (92%) and stereocontrol (92.5 : 7.5 er). In sharp contrast, no reaction was observed when DCE was used alone as the solvent (Fig. 2, entry 15). Enantioselectivity increased as the reaction temperature was lowered to 0 °C (Fig. 2, entry 16), and surprisingly, the enantiomeric ratio improved to 96 : 4 despite low conversion (48% yield). Finally, lowering the reaction temperature to 0 °C, increasing the catalyst loading to 10 mol%, and prolonging the reaction time to 48 h gave the best result (90% isolated yield and 96 : 4 er, entry 17).

Fig. 2 Reaction condition optimization. General reaction conditions: 1 (0.1 mmol), HBpin (1.5 equiv.), [RhCl(cod)]₂ (2 mol%), ligand (4 mol%), LiOAc (30 mol%), solvent (0.5 mL), T = 70 °C, 12 h. ^aIsolated yield. ^bEr were determined by HPLC on a chiral stationary phase. ^c[RhCl(cod)]₂ (5 mol%), ligand (10 mol%), 48 h. ^dUsing (S,S,S,S)-L6 as ligand. TIPS = triisopropylsilyl, TMS = trimethylsilyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl.

With the optimal reaction conditions in hand, we next explored the substrate scope of silyl enol ethers for this rhodium-catalyzed asymmetric remote hydroboration. As shown in Fig. 3, a diverse set of silyl enol ethers successfully participated in this enantioselective remote hydroboration, providing the corresponding 1,n-diol products in good yields and excellent enantioselectivities. The boronic esters were oxidized to the corresponding diols for ease of separation and determination of er. The mild reaction conditions were applicable to a broad range of linear alkyl silyl enol ethers with different chain lengths (2a–2g). It is worth mentioning that extra long-distant proceeded smoothly to furnish 1,12-diol 2e in 89% yield and 94 : 6 er from phenyldodecanone-derived silyl enol ether under the standard reaction conditions. Importantly, an array of trisubstituted silyl enol ethers with different substituents at different positions on the phenyl ring underwent asymmetric isomerization/hydroboration to afford the valuable diol products in good efficiency. As described in Fig. 3, numerous substituents at para-position such as –Me (2h), –OMe (2i), and –Ph (2j) were well tolerated, leading to the corresponding diols in good yields and ers. Additionally, although the substrate 1k with F at ortho-position gave a lower yield (46%) due to the low conversion, it exhibited a subtle influence on the enantioselectivity (89 : 11 er). Of particular note was that a broad range of functional groups including electron-donating groups and electron-withdrawing groups (2l–2v), such as –Ph, –CH₂OBn, –OMe, –F, –Cl, –Br, –CF₃, –OCF₃, and –TMS, were all compatible under the mild reaction conditions, providing the corresponding products in 92 : 8–98 : 2 ers. Gratifyingly, a range of functional groups that readily undergo downstream functionalizations such as –Bpin, –OH, –TMS, acetal, and Bn-protected alcohol could all be well accommodated to afford the desired products in moderate yields (50–65%) and good enantioselectivities (2w–2ab). Notably, a free phenolic group (1x) was compatible, and the corresponding product 2x was provided in moderate yield and high enantioselectivity (50%, 95 : 5 er). In addition to the phenyl groups, other aromatic substituents such as naphthalene, fluorene, and furan could also be successfully incorporated into the products (2ac–2ag). To further demonstrate the applicability of this protocol, an array of silyl enol ethers derived from complex molecules were subjected to the established optimal conditions. We were pleased to find that the silyl enol ethers bearing dihydro cholesterol, estradiol, and (–)-menthol all underwent this enantioselective hydroboration to afford the diol products (2ah–2aj) in good yields and diastereoselectivities. The use of (S,S,S,S)-L6 ligand gave the ent-2ai and ent-2aj good yields and diastereoselectivities. The reaction of dialkyl-substituted enol silyl ether 1ak under standard conditions afforded racemic 2ak. Pleasingly, the use of (S)-DTBM-Segphos instead of L6 gave the desired product in 40% yield and moderate enantioselectivity (77 : 23 er).

Fig. 3 Scope of Me-terminated silyl enol ethers. General reaction conditions: 1 (0.2 mmol), HBpin (1.5 equiv.), [RhCl(cod)]₂ (5 mol%), ligand (10 mol%), LiOAc (30 mol%), THF/DCE (0.8/0.2 mL), 0 °C, 48 h. Isolated yield. ^aUsing (S,S,S,S)-L6 as ligand. ^bUsing hexane/2-methyl tetrahydrofuran/DCE (0.6/0.2/0.2 mL) as solvent. ^cWithout oxidation. ^dThe substrate is 1x (see supporting information for details); HBpin (2.5 equiv.). ^eDr was determined by HPLC. ^f1ak (0.2 mmol), HBpin (5.0 equiv.), [RhCl(cod)]₂ (5 mol%), (S)-DTBM-Segphos (10 mol%), LiOAc (2.0 equiv.), THF (1.0 mL), 110 °C, 48 h. Isolated yield.

Based on the success of enantioselective remote borylation of methyl-terminated silyl enol ethers, the generality of Rh-catalyzed asymmetric migratory borylation was further evaluated by more challenging substrates, i.e., non-methyl-terminated SEEs, which will be confronted with enantioselective, diastereoselective, and regioselective control issues. Pleasingly, as described in Fig. 4, we found that Ph-substrate 3a reacted smoothly with HBpin to give the corresponding product 4a in good yield (89%), high enantioselectivity (97 : 3 er), and reasonable diastereoselectivity under the optimized conditions. Moreover, an array of aryl-terminated substrates, with various substituents at different positions on the phenyl ring, underwent the desired asymmetric remote hydroboration, yielding valuable diol products with high efficiency. Various substituents at para- or meta-positions including electron-donating groups and electron-withdrawing groups (4b–4l), such as –Me, –OMe, –CF₃, –F, –Cl, –OTBS and –Bpin were all compatible under the mild reaction conditions, providing the corresponding products in 95 : 5 to 99 : 1 er. The moderate yield of para-phenyl-substituted substrate (51%) is due to the formation of hydrogenated products. Besides, the efficiency of migration is not affected by the alkyl chain length (4m–4p), and the corresponding products were provided with good yields and enantioselectivities. It's worth noting that 4p could be obtained with good diastereoselectivity (12 : 1 dr). To our delight, the indole-terminated silyl enol ether (3q) can be converted to product 4q successfully with good yield (70%) and excellent enantioselectivity (98 : 2 er). When isopropyl and 3-pentyl terminated silyl enol ethers (3r) and (3s) were treated with the optimized conditions, the isomerization was not affected, delivering the methyl borylation products efficiently. Silyl groups can also be used as terminating groups to furnish the corresponding diol (3w) in moderate yield and 91 : 9 er. Notably, we found that the boron was installed at the β position rather than the α position when the OTBS-terminated substrate (3t) was used, probably due to the steric hindrance. Besides, silyl enol ethers 3u and 3v with Bpin at the end of an alkyl chain, regardless of the chain length, were competent substrates, providing the gem-diboronate products with high efficiency. As expected, the fluorine (F) at the terminal position (3x) was incompatible, leading to the formation of the diol product 2b in 38% yield (poor conversion) via defluorination.²⁰

Fig. 4 Scope of R-terminated silyl enol ethers. Reactions conditions: 3 (0.2 mmol), HBpin (1.5 equiv.), [Rh(cod)Cl]₂ (2 mol%), ligand (4 mol%), LiOAc (30 mol%), THF/DCE (0.8/0.2 mL), 30 °C, 48 h. Dr was determined by analysis of ¹H NMR spectra of unpurified mixtures. Er values of the major diastereoisomers are shown, and the er values of the minor diastereoisomers are shown in the SI. ^aUsing (S,S,S,S)-L6 as ligand. ^bThe substrate is 3l (see SI for details). ^c0 °C; ^dDr was determined by analysis of HPLC spectra. ^eWithout oxidation. ^f1H NMR yield.

The alkyl boronates are versatile building protocol that might serve as a powerful platform to convert C(sp³)–H bonds into a variety of functional groups via the alkyl boronates generated in Fig. 5 by this asymmetric remote C(sp³)–H borylation. To demonstrate this point, a series of synthetic transformations of 2a′ were studied. First, a gram-reaction of substrate 1a (3.0 mmol) was carried out, which proceeded smoothly to afford the desired alkyl boronate 2a′ in 88% yield and 96 : 4 er. Subsequently, Pd-catalyzed Suzuki–Miyaura²¹ coupling of 2a′ with 4-bromotoluene was conducted, affording the product 7 in 85% yield and 96 : 4 er (Fig. 5a-i). The product 2a′ was then treated with the protocol developed by Aggarwal,²² delivering the bromination product 8 in excellent yield (95%) and 96 : 4 er (Fig. 5a-ii). Furthermore, the amination reaction of boronate 2a′ via the protocol developed by Liu²³ was achieved in the presence of NH₂–DABCO and KO^tBu, and the subsequent protection with TFAA gave the synthetically valuable amnio alcohol product 9 in 60% yield and 96 : 4 er (Fig. 5a-iii). The treatment of 2a′ with vinyl magnesium bromide and I₂ successfully furnished the desired product 10 in 84% yield and 95 : 5 er (Fig. 5a-iv), which could undergo further C=C bond functionalization to give a more complex fragment.²⁴ Considering that various types of 1,n-diols can be readily prepared via this enantioselective isomerization and hydroboration, and are widely applied in organic synthesis, the use of 1,4-diol 11 as a valuable building block for the synthesis of chiral 12 (ref. 25) and lactone 13 (ref. 26) was also demonstrated, suggesting this method may find broad applications in the synthesis of pharmaceutical and bioactive molecules, given the ubiquity of tetrahydrofuran and lactone skeletons.

Fig. 5 (a) Synthetic transformations. Gram-scale reaction: 1a (3.0 mmol), HBpin (1.5 equiv.), [RhCl(cod)]₂ (2 mol%), (R,R,R,R)-L6 (4 mol%), LiOAc (30 mol%), THF/DCE (12.0/3.0 mL), 0 °C, 48 h. (i) [Pd₂(dba)₃] (2 mol%), Ruphos (4 mol%), 4-bromotoluene (1.0 equiv.), NaO^tBu (3.0 equiv.), toluene/H₂O, 80 °C, 24 h. (ii) 3,5-Bis(trifluoromethyl)bromobenzene (1.5 equiv.), ⁿBuLi (1.5 equiv.), NBS (1.5 equiv.), THF, −78 °C to RT. (iii) KO^tBu (1.8 equiv.), NH₂-DABCO (1.2 equiv.), THF, 80 °C, 16 h, then TFAA (1.2 equiv.), 80 °C, 2 h. (iv) Vinylmagnesium bromide (4.0 equiv.), I₂ (4.0 equiv.), THF/MeOH, −78  °C to RT, 10 h. (v) 1b (3.0 mmol), HBpin (1.5 equiv.), [RhCl(cod)]₂ (2 mol%), (R,R,R,R)-L6 (4 mol%), LiOAc (30 mol%), THF/DCE (12.0/3.0 mL), 0 °C, 48 h; NaOH/H₂O₂ (1.5 equiv.), THF, 0 °C, 0.5 h; Then TBAF (1.5 equiv.), THF, 0 °C, 10 min. (vi) NaH (1.5 equiv.), PO(OMe)₃ (1.2 equiv.), CPME, RT, 12 h. (vii) RuH₂(PPh₃)₄ (10 mol%), (E)-4-phenylbut-3-en-2-one (2.0 equiv.), toluene, RT, 24 h. (b) Synthetic applications. See more details in the SI. Boc = tert-butoxycarbonyl, NBS = N-bromosuccinimide, TFAA = trifluoroacetic anhydride, TBAF = tetrabutylammonium fluoride, DABCO = triethylenediamine. DMAP = 4-dimethylaminopyridine, DIPEA = N,N-diisopropylethylamine, MsCl = methanesulfonylchloride.

The synthetic utilities of this approach were further demonstrated by the synthesis of chiral pharmaceutical molecules and catalysts. Starting from chiral alkyl boronate 2a′, (R)-fluoxetine, an antidepressant, was prepared in 65% yield and 94 : 6 er via the amination²⁷ with MeONH₂ and ⁿBuLi, the reduction with LiAlH₄, and the S_NAr reaction with 4-fluorobenzotrifluoride (Fig. 5b). In addition, dapoxetine, which is used to treat male sexual dysfunction, was successfully synthesized with good yield and excellent enantioselectivity (97.5 : 2.5 er). The synthesis involved Ts-protection of 1,3-diol, an S_NAr reaction with 1-naphthol, followed by protection and an S_N2 reaction with dimethylamine hydrochloride. It is worth noting that chiral amino alcohol 17, as a versatile synthon, could be prepared in high efficiency via the asymmetric migratory hydroboration of silyl enol ether 1a and could be used in the synthesis of organic catalyst 19 (ref. 28) through the amination of chlorobenzothiazole and the cyclization of intermediate 18.

Control experiments for stereoselectivity were conducted to investigate the geometry effect of the carbon–carbon double bond (Fig. 6a). Substrate 1s was used as a model substrate because Z-1s and E-1s can be separated by column chromatography. Under the standard conditions, Z-1s reacted smoothly with HBpin to give the product ent-2s in 87% yield and 97 : 3 er (Fig. 6a, eqn (1)). The use of E/Z mixture led to the isolation of ent-2s in 39% yield and 97 : 3 er, and 52% of 1s recovered (E/Z = 16/1) (Fig. 6a, eqn (2)). Additionally, only a trace amount of ent-2s was observed when 1s (E/Z = 16/1) was subjected to the standard reaction conditions (Fig. 6a, eqn (3)). These results suggest that the reaction proceeds stereospecifically, as the significant steric hindrance likely prevented the coordination of the Rh–H complex to alkenes or the subsequent migratory insertion step.

Fig. 6 (a) Control experiments. (b) Deuterium-labeling experiments. (c) Control experiments for non-dissociative chain walking process. ^aDr was determined by analysis of HPLC spectra.

To confirm this viewpoint about the contra-thermodynamic isomerization, allylic silyl ether I was prepared and subjected to the standard reaction conditions. The reaction proceeded smoothly to afford racemic 2a′ in 72% yield without forming the isomerization product 1a (Fig. 6a, eqn (4)), likely due to Rh–H migratory insertion into allylic silyl ether I favored 2a′ formation due to steric hindrance. To complement the experimental findings, density functional theory (DFT) calculations were then carried out. The enthalpy and Gibbs free energy of silyl enol ether 1a and allylic silyl ether I were calculated. As shown in Fig. 1d, the silyl enol ether 1a is more stable than the corresponding allylic silyl ether I by 12.5 kcal mol⁻¹, indicating that the isomerization from 1a to I is a contra-thermodynamic process, and the irreversible terminal hydroboration provides the driving force for this contra-thermodynamic isomerization. To gain more insights into the reaction mechanism, we carried out a series of deuterium-labeling experiments. The reaction of 1a with DBpin under the standard conditions proceeded smoothly to afford product d-2a in 94% yield, and deuterium incorporation was observed along the carbon chain (38%, 10%, 2%, 5% and 5%), respectively (Fig. 6b, eqn (1)). This result was consistent with the chain-walking mechanism. Likewise, the use of deuterated silyl enol ether 1a-d₁ resulted in the formation of 2a-d₁ in 92% yield with 10%, 4%, 50%, 12% and 12%, D atom incorporation at the shown positions (Fig. 6b, eqn (2)). The reaction of 1a-d₃ with HBpin under the standard conditions afforded product 2a-d₃ in 86% yield with 78%, 50%, 82% and 82% D atom incorporation at the α- and β-positions of a hydroxyl group (Fig. 6b, eqn (3)). The successful formation of d-2b from vinyl ether 1b′ with 10%, 10%, and 9% D atom incorporation further verified the chain-walking process (Fig. 6b, eqn (4)). Based on these experimental results, we speculated that the migratory insertion of Rh–H into the silyl enol ether is not regioselective, but is irreversible, which might account for the D incorporation at the benzylic position in 2a-d₁. Moreover, the chain walking process (iterative migratory insertion and β-H elimination) is reversible based on the deuterium labeling experiments. In addition, a cross-experiment between 1a-d₁ and 1m was conducted, providing product ent-2m in 80% yield without D incorporation (Fig. 6c, eqn (1)). Finally, control experiments using (rac)-3y and (R)-3y revealed distinct selectivity. (rac)-3y gave 4y with 1 : 1 dr, 91 : 9 er and 91 : 9 er (Fig. 6c, eqn (2)), while (R)-3y afforded 4y with 8 : 1 dr and er values of 99 : 1 and 82 : 18 (Fig. 6c, eqn (3)). These results indicated a non-dissociative chain-walking mechanism.⁸

To further shed light on the reaction mechanism, a set of kinetic experiments were carried out by using the initial rate method (Fig. 7a). As depicted, an inverse KIE of 0.98 was obtained when deuterated silyl enol ether 1a-d₁ was subjected to the standard conditions (Fig. 7a-I and II), indicating that the migratory insertion of Rh–H into the silyl enol ether is less likely rate-limiting because hybridization change from sp² to sp³ was involved in this step. Moreover, the measurement of the reaction rates with HBpin and DBpin revealed a KIE of 1.35 (Fig. 7a-I and III), suggesting that the B–H bond cleavage is less likely to be rate-determining. Besides, the KIE experiment of deuterated silyl enol ether 1a-d₃ with HBpin was explored, giving a KIE of 2.8 (Fig. 7a-I and IV) and indicating that β-hydride elimination may be the rate-limiting step.²⁹ Finally, kinetic experiments were carried out. We found that the reaction exhibited a first-order dependence on the catalyst, as well as on both 1a and HBpin (Fig. 7b). These results suggested that β-hydride elimination likely contributed to the rate-limiting step.

Fig. 7 (a) Kinetic isotope effect experiments. (b) Kinetic order determinations.

Based on the experimental results, a plausible reaction mechanism is proposed, as illustrated in Fig. 8. The catalytic cycle initiates with the coordination of [Rh(cod)Cl]₂ with chiral ligand L* and LiOAc to form a rhodium complex. Subsequent reaction with HBpin yields the key Rh–H species A. Migratory insertion of Rh–H species A into the substrate 1a generates intermediate B, which undergoes β-hydride elimination to afford the isomerized alkene complex C. Finally, reinsertion followed by metathesis with HBpin releases product 2a′ and regenerates the active Rh–H species A, thereby completing the catalytic cycle.

Fig. 8 Proposed mechanism cycle.

Conclusions

In conclusion, we have developed a novel catalytic asymmetric isomerization/hydroboration of silyl enol ethers under mild reaction conditions, providing an efficient method for the construction of enantioenriched and synthetically-valued borylethers. This reaction showed a broad substrate scope of silyl enol ethers and good functional group tolerance. Notably, various terminated groups, such as Me, Ar, protected alcohol, oxygen, boron, and silicon, were all compatible with delivering the value-added corresponding diols efficiently. This reaction overcomes the thermodynamically unfavorable isomerization, β-oxygen elimination, and the challenging regioselectivity and enantioselectivity control. Notably, the chiral borylether products can be converted to various value-added building blocks, such as halides, alkenes, 1,n-diol, lactones, and oxyheterocyclic rings. The practicability of this protocol in medicine and organic synthesis was also demonstrated by the successful synthesis of organic catalysts and drug molecules, including dapoxetine and fluoxetine. Preliminary mechanistic studies revealed that a nondissociative chain-walking process was involved, with the β-hydrogen elimination possibly contributing to the rate-limiting step. Further research on enantioselective contra-thermodynamic reactions and their applications is currently ongoing in our laboratory.

Author contributions

W. Z. conceived the project and directed the work. W. Z., Y. Y. and J. L. wrote the paper. Y. Y. and J. S. prepared the supplementary information. Y. Y. and J. S. performed the experiments.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the SI: synthetic details, characterization of products and substrates, and computational details. See DOI: https://doi.org/10.1039/d5sc04819b.

Acknowledgements

We thank Y. X. (HNU) for the experimental assistance, C. L. (GZU) for assistance with the preparation of the manuscript and supporting information. We thank the National Natural Science Foundation of China (Grant No. 22271086, U24A20481 and 21971059), the National Program for Thousand Young Talents of China, the National Natural Science Foundation of China (32360689), the Science and Technology Project of Hunan Province (2024JJ3006) and the Hunan Provincial Innovation Foundation for Postgraduates (No. CX20230413).

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